A Systematic Review of Self-Management Interventions for Patients with Inflammatory Bowel Disease

Abstract

Introduction

Previous studies have reported the effectiveness of inflammatory bowel disease (IBD) self-management. However, it is unclear which types of self-management interventions are effective. We conducted a systematic literature review to clarify the status and efficacy of self-management interventions for IBD.

Methods

Searches were performed in databases including Embase, Medline, and Cochrane Library. Randomized, controlled studies of interventions in adult human participants with IBD involving a self-management component published in English from 2000 to 2020 were included. Studies were stratified based on study design, baseline demographic characteristics, methodological quality, and how outcomes were measured and analyzed for statistically significant improvements in outcomes, such as psychological health, quality of life, and healthcare resource usage.

Results

Among 50 studies included, 31 considered patients with IBD and 14 and 5 focused on patients with ulcerative colitis and Crohn’s disease, respectively. Improvements in an outcome were reported in 33 (66%) studies. Most of the interventions that significantly improved an outcome index were based on symptom management and many of these were also delivered in combination with provision of information. We also note that among effective interventions, many were conducted with individualized and patient-participatory activities, and multidisciplinary healthcare practitioners were responsible for delivery of the interventions.

Conclusion

Ongoing interventions that focus on symptom management with provision of information may support self-management behavior in patients with IBD. A participatory intervention targeting individuals was suggested to be an effective intervention method.

Introduction

Inflammatory bowel disease (IBD) is a collective term for chronic diseases involving inflammation of the gastrointestinal tract with repeated exacerbations and remissions. IBD typically refers to two diseases, ulcerative colitis and Crohn’s disease, both of which have unclear etiologies thought to arise from complex interactions of genetic and environmental factors. Unpredictable flaring of IBD restricts patient’s daily life and affects quality of life (QOL) and social life, such as study and work and psychological health [1, 2]. IBD often develops at a young age and with no radical treatment currently available, patients must cope with symptoms throughout their lives. The prevalence of IBD in Asian countries has recently been increasing and rises are expected in healthcare and economic costs.

The importance of self-management in patients with chronic diseases has been recognized and is defined as an “individual’s ability to manage the symptoms, treatment, physical and psychological consequences, and lifestyle changes inherent in living with a chronic disease” [3]. Self-management also includes the patient’s ability to monitor their condition and maintain a good QOL.

Interventions that aim to improve a patient’s self-management ability have been developed and effectively applied for chronic diseases such as heart disease, diabetes mellitus, and rheumatoid arthritis [3, 4]. Numerous studies have examined effects of self-management interventions, including traditional educational lectures and cognitive behavioral therapy, on management of symptoms, stress, and QOL in patients with IBD [5–10]. However, Barlow et al. and Conley et al. recognized that the nature of the intervention and the types of outcomes assessed varied widely among such studies [11, 12].

Previously, Tu et al. [13] conducted a meta-analysis of literature published prior to 2015 to identify the most effective components of self-management interventions for improving health-related QOL in patients with IBD [13]. They reviewed 15 studies, all of which assessed health-related QOL using only the Inflammatory Bowel Disease Questionnaire (IBDQ), and found that distance or remote self-management programs led to better QOL than other types of interventions. However, they did not assess how different self-management interventions may impact additional outcomes in IBD, including symptom severity and healthcare resource utilization. Healthcare resource utilization may be a useful outcome measure to evaluate self-management [14, 15].

Thus, we performed an updated and expanded systematic review with the aim of identifying which self-management interventions are effective for a range of patient outcomes in IBD, including symptom severity and use of healthcare resources (e.g., healthcare provider [HCP] visits, hospitalizations, email/telephone consultations; online suppl. Table S1; for all online suppl. material, see www.karger.com/doi/10.1159/000530021).

Methods

We conducted a systematic review using the Cochrane methodology [16] and reported our findings according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA).

Eligibility Criteria

We included randomized controlled trials of interventions that involved a self-management component. The outcome measures of interest were QOL, patient-reported outcomes (including self-efficacy), healthcare resource use, and behavior modification. The review targeted studies involving human participants with IBD aged ≥18 years. No limitations were placed on the study setting or timeframe. Only studies published in English from 2000 to 2020 were selected. Hence, the primary reasons for exclusion of studies were recorded as not humans, not relevant population, not relevant intervention, not relevant outcome, not relevant study design, not relevant language, and duplicated study.

Information Sources

We searched the following electronic databases: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid Medline(R) (access via the OVID interface), Embase (access via the OVID interface), Cochrane Library (CENTRAL, via Wiley Interscience, PsychInfo, and CINAHL). Titles and abstracts from the following websites were also hand-searched (from 2019 to 2020) and relevant full-text articles were assessed to capture studies not mentioned in the databases (M.N.): The American Journal of Gastroenterology, European Crohn’s and Colitis Organisation, Value in Health (ISPOR).

Search

Our initial search syntax for Medline and Embase is detailed in online supplementary Table 2 and that for the Cochrane Library is detailed in online supplementary Table 3. The searches were performed on June 2 and 3, 2020, respectively.

Study Selection

The study selection was performed with assistance from a commercial consultancy group, Creativ-Ceutical Ltd. (Tokyo, Japan). References were imported into an EndNote database and duplicated articles were eliminated. The database was imported and saved in DistillerSR software for screening of titles and abstracts, and full-text review. Lists of titles and abstracts were screened by two independent reviewers (Creativ-Ceutical) according to the defined inclusion and exclusion criteria. Lists obtained from the two reviewers were combined and discrepancies resolved by a third reviewer (Creativ-Ceutical). Any article meeting the inclusion criteria, or which could not be excluded based on the abstract, was subject to full-text review. Full-text articles were evaluated by two independent reviewers to verify conformity with the inclusion criteria (Creativ-Ceutical). Discrepancies were resolved by a third reviewer (Creativ-Ceutical). All references and reviewer decisions were saved in DistillerSR, and the database was also exported and saved as an Excel file.

Data Extraction

Data from studies meeting the criteria specified above were extracted into an Excel file and tabulated with relevant characteristics and outcomes. One analyst extracted the data, and a second analyst validated the accuracy of the extracted data, which included:

• •Publication details: first author, journal, and year of publication; study name (if any)
• •Study design: e.g., country, objective, study type, data source, time period, number of patients
• •Baseline characteristics: e.g., gender, age, weight, geographic region
• •Overall methodological quality of study (e.g., allocation concealment, percentage of follow-up, adherence to principle of intention-to-treat analysis, a priori sample size calculation)
• •Results: improvement measured by relevant instruments assessing: QOL, patient-reported outcomes, behavior modification.

Risk of Bias Assessment

Creativ-Ceutical, Ltd. performed a quality appraisal of each study using the Cochrane risk of bias tool checklist [16]. This included assessment of bias from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcome, and bias in selection of the reported result. The risk of bias was determined by one reviewer, while another reviewer validated the accuracy of assessment. Discrepancies were resolved via discussion. Where possible, blinding implemented in the studies was also noted.

Classification of Interventions

Two reviewers (M.I., L.H.) classified the type of interventions and their outcomes based on the definitions used by Barlow et al. [3] (online suppl. Table 4). Barlow et al. [3] classified self-management of chronic diseases into information, drug management, symptom management, management of psychological conditions, lifestyle, social support, communication, and other self-management strategies.

Classification of Outcome Measures

Barlow et al. [3] classified the outcomes of self-management studies into 10 categories: physical health status, psychological health status, QOL/health status, medication, knowledge, laboratory tests, self-efficacy, self-management behaviors, health care resources, and cost (online suppl. Table 1).

Classification of Intervention Style

The reviewers (M.I., L.H.) classified the style of interventions as: lecture (i.e., attending a lecture as a passive participant), participation (i.e., taking part in interactive activities), or both; individual (i.e., delivered on a one-to-one basis), group (i.e., delivered to a group), or both; and 1-time or series (i.e., delivered on more than one occasion). When an assignment was unclear, the study was marked as unknown. Types of HCPs involved in the interventions were also examined [17]. Information on the types of HCPs engaged in the interventional trials was collected from literature and where no clear description was included, the status was designated unknown.

Synthesis

Studies that reported statistically significant differences between the intervention and control groups in at least one outcome were considered to have significant outcomes (we accepted the level of significance defined by the investigators in the individual studies, which was typically p < 0.05).

Results

The initial search yielded 916 articles after removal of duplicates (Fig. 1). A further 800 articles were excluded after screening of titles and abstracts. Full-text screening was applied to the remaining 116 articles and 46 articles fulfilled the selection criteria. An additional 4 articles from other sources were identified from the hand literature search. Two articles, by Cramer et al. [18] and Koch et al. [19], reported different aspects of the same clinical trial and patient groups. A further 2 articles by Mikocka-Walus et al. [7] also involved the same patients but included different aspects of the same trial after 1- and 2-year follow-up [7, 8]. For the purposes of our analysis, we considered both sets of articles to be different reports giving a total of 50 studies included in the analysis (online suppl. Table 5).

Fig. 1.

Summary of study flow.

Risk of Bias

In almost all studies, the methods of measuring outcomes were appropriate and results for all outcomes defined in the protocol were presented. Three studies (6%) were graded as having an overall high risk of bias [6, 20, 21], twelve (24%) were graded as having some concerns [7–10, 22–29], and the remaining thirty-five (70%) were graded as low risk of bias (Fig. 2; online suppl. Table 6) [18, 19, 30–62]. The most common issues identified were related to missing information from the study, which at a minimum, raised concerns in 16 of the studies (32%).

Fig. 2.

Risk of bias analysis.

Study Characteristics

We identified 31 studies related to interventions in patients with IBD [7–10, 20, 21, 23–25, 27, 30, 33–35, 39–42, 44, 45, 48, 49, 52–55, 57–61], and 14 and 5 studies specifically focused on patients with ulcerative colitis [18, 19, 22, 26, 29, 32, 36–38, 43, 46, 47, 50, 51] and Crohn’s disease [6, 28, 31, 56, 62], respectively (online suppl. Table 5). Almost 70% of the studies (n = 34) were from European countries [6, 10, 18, 19, 21–24, 26–28, 32–36, 38, 39, 41–43, 45, 47, 49, 52–54, 56–62], with a smaller proportion from other Western countries, including 12% (n = 6) from the USA [30, 31, 37, 48, 50, 51] and 4% (n = 2) each from Canada [40, 44], New Zealand [20, 55], and Australia [7, 8]. There was 1 study (2%) each from Brazil [9], China [29], Israel [25], and Iran [46].

Classification of Interventions

The studies were assigned to one or more categories of intervention (online suppl. Table 4). The most common category was information provision (n = 27), followed by management of psychological effects (n = 26), other (n = 23), symptom management (n = 17), lifestyle (n = 8), communication (n = 4), social support (n = 1), and drug management (n = 1). Among inventions with a component categorized as other, common subcategories included group psychotherapy (n = 10); coping strategies (n = 7); problem-solving, action planning, and spirituality (n = 6 for each); and 1 study involved goal setting (subcategories are not mutually exclusive).

Classification of Outcomes

Of the 50 studies, 30 evaluated physical health status. A total of 34 reports evaluated psychological health status where the most common instrument was the Hospital Anxiety and Depression Scale (HADS) (n = 12) (online suppl. Table 1). QOL/health status was examined in 49 studies: of these, 32 used the IBDQ. In addition, outcome measures of included studies were categorized as medication (n = 2), knowledge (n = 8), laboratory tests (n = 10), self-efficacy (n = 15), self-management behaviors (n = 8), health care resources (n = 5), and cost (n = 1), respectively. A further 15 studies were identified that included measures of patients’ perceptions of the program.

Effective Interventions and Improved Outcomes

There were 33 studies in which at least 1 outcome measure had a significant difference (Table 1; Fig. 3). Among these 33 studies, 18 interventions contained elements of management of psychological consequences and 17 interventions contained elements of “other.” Subsequently, there were 16 reports of interventions classified as information, 14 of interventions classified as symptom management, 5 of interventions classified as lifestyle, and 2 of interventions classified as communication. Among the 33 studies, 12 involved a combination of 2 intervention categories [18, 25, 33, 38, 42, 46, 49–53, 55]. Notably, studies that combined the intervention types classified as information and symptom management showed improvements in their outcome measures (10 out of 11 reports) [25, 31, 37–39, 42, 43, 46, 49, 55]. There appeared to be many combinations with psychological interventions with those falling into the “other” category (Fig. 3). However, the other category includes various intervention types and the number of overlapping studies here was small when considering individual subcategories. Therefore, the most common combination was between information and symptom management.

Table 1.

Summary of 33 articles with significant outcomes with their intervention type components

	Intervention								Outcome type
Author, year	Information	Management psychological consequences	Drug management	Lifestyle	Symptom management	Social support	Communication	Other	Physical health status	Psychological health status	QOL/health status	Medication	Knowledge	Laboratory tests	Self-efficacy	Self-management behaviors	Healthcare resources	Cost
Robinson et al., 2001 [43]	○				○			○	○								○	○
Borgaonkar et al., 2002 [44]	○										○
Kennedy et al., 2003 [36]	○												○
García-Vega et al., 2004 [28]	○	○						○	○
Kennedy et al., 2004 [39]	○				○			○		○							○
Elsenbruch et al., 2005 [32]		○		○				○
Waters et al., 2005 [40]	○									○	○		○				○
Langhorst et al., 2007 [22]		○		○	○				○		○
Elkjaer et al., 2010 [38]	○				○						○
Boye et al., 2011 [34]		○			○			○			○
Cross et al., 2012 [37]	○				○			○			○
Keefer et al., 2012 [31]	○	○		○	○		○	○		○	○				○
Mizrahi et al., 2012 [25]		○			○					○	○
Keefer et al., 2013 [50]		○						○	○
Berrill et al., 2014 [33]		○						○			○
Hueppe et al., 2014 [41]	○				○			○			○					○	○
Jedel et al., 2014 [51]		○						○		○	○
Gerbarg et al., 2015 [48]		○			○			○	○	○	○
Klare et al., 2015 [54]				○							○
Schoultz et al., 2015 [53]		○						○		○
McCombie et al., 2016 [20]		○								○	○
Berding et al., 2017 [61]	○						○	○		○
Cramer et al., 2017 [18]		○						○		○			○			○
de Jong et al., 2017 [42]	○				○					○	○					○	○
Evertsz et al., 2017 [60]		○								○	○
Hu et al., 2017 [29]	○	○		○						○	○
Lee et al., 2017 [57]								○			○
Del Hoyo et al., 2018 [49]	○				○				○							○	○
Artom et al., 2019 [21]		○							○
Hunt et al., 2019 [30]		○								○	○
Magharei et al., 2019 [46]	○				○					○
Wynne et al., 2019 [52]		○						○		○
McCombie et al., 2020 [55]	○				○												○

Fig. 3.

Network diagram showing common statistically significant intervention combinations (across ≥2 studies). Area of each node represents the number of articles and the thickness of lines between nodes represents the number of studies sharing the combination, where “Other” includes: accessing support services, action plans, career planning, contracting, coping, decision making, goal setting, group psychotherapy, managing uncertainty, problem-solving, rational-emotive therapy, and spirituality (online suppl. Table 4).

Furthermore, improvements were reported in 87.5% (7/8) of studies that examined use of healthcare resources by patients (i.e., hospitalization rate, surgery rate, emergency outpatient visit rate, and consultation rate with HCPs) [28, 39–43, 49, 55]. Among these, 6 studies included interventions in both information provision and symptom management [39, 41–43, 49, 55].

Of interventions classified under information that reduced healthcare resource utilization, Waters et al. [40] found that patients who had attended a formal education program based on distribution of pamphlets and ad hoc education from physicians during clinic visits before the study had significantly lower healthcare use (t = −1.23, p = 0.03). Patients receiving the education also reported greater satisfaction with the program than did the control group (t = −3.45, 0.001) [40]. Studies by de Jong et al. [42], Del Hoyo et al. [49], and McCombie et al. [55] employed interventions implemented through telemedicine systems (custom webpage/smartphone applications) that provided tailored information and tools for symptom management and reported outcome measures of hospitalization rate, number of visits, and number of consultations. De Jong et al. [42] reported a significantly lower mean number of outpatient visits to the gastroenterologist or nurse in the telemedicine group (1.55 [standard deviation 1.50]) than in the standard care group (2.34 [1.64]; difference −0.79 [95% CI: −0.98 to −0.59]; p < 0.0001), as well as fewer mean number of hospital admissions (0.05 [0.28] vs. 0.10 [0.43]; difference −0.05 [−0.10 to 0.00]; p = 0.046) at 12 months [42].

Among the 50 studies, interventions based on patient participation and individual activities were more common than lectures (Fig. 4a). In the interventions categorized as information, management of psychological consequences, symptom management, and other, many of the patient-participatory and personalized interventions improved outcomes of the studies (Fig. 4b). Figure 4c shows the number of studies of single and repeated interventions.

Fig. 4.

Total number of studies (unfilled bars) classified by intervention style and type, with proportion of studies having statistically significant outcomes indicated by solid shading. a Lecture and participation. b Group and individual. c Number of occasions. d Delivery team. HCP, health care provider.

In at least 42 studies, interventions were conducted by more than one type of HCP (Fig. 4d), including gastroenterologists, gastrointestinal nurses, and psychologists. In the 33 studies that reported statistically significant differences in one or more outcomes, 31 involved HCPs or specialists other than physicians. Among these, psychologists were most commonly involved (n = 14) [20, 21, 25, 28, 30, 31, 33, 34, 41, 50, 52, 57, 60, 61]. This included 8 studies where cognitive behavior therapy resulted in improved patient QOL [20, 21, 30, 31, 33, 34, 52, 60]. Nurses were involved in 9 of the 31 reports of effective interventions [21, 29, 34, 37, 39, 40, 42, 49, 55]. Six of these nine studies reported improvements in patients’ QOL [21, 29, 34, 37, 39, 40] and three reported decreases in hospital visits, hospitalization rate, and number of consultations [42, 49, 55].

Discussion

This review draws upon the experiences of a wide variety of clinical interventions aimed at supporting patients with IBD to develop self-management behaviors. Of the 50 studies included in this review, 33 (66%) reported effective self-management interventions in one or more measured outcomes. Notably, among effective interventions, a large proportion included a component of symptom management. Particularly, interventions that combined symptom management with information, patients reported clear positive effects on use of healthcare resources and psychological well-being. Additionally, many effective interventions were conducted with individualized and patient-participatory activities. A range of HCPs was responsible for delivery of the interventions, and in many cases multiple professionals, other than the physician, handled different aspects of the delivery.

Symptom Management with Information Provision and Education

As Barlow et al. [3] reported, components of self-management of chronic diseases typically target the management of stress, diet, fatigue, and pain and highly individualized elements such as recognizing one’s problem and working proactively to address issues that arise, self-efficacy, and identifying solutions from past experiences. We found that most interventions that significantly improved an outcome index were based on symptom management and many of these were also delivered in combination with provision of information. Here, provision of information, as defined by Barlow et al. [3], relates to provision of educational interventions to inform patients about the disease and care of their condition. For chronic diseases other than IBD, it has been shown that patients gaining knowledge about their disease improves their symptoms and reduces medical expenses. With regards to IBD, Quan et al. [63] reported that educational interventions improve patient knowledge about their disease. In contrast, in a recent study, Borgaonkar et al. [44] found that short-term health-related QOL deteriorated on provision of knowledge. Barlow et al. [11] concluded that information typically improves patient knowledge and there is a need to establish the role of education in treatment of IBD. In a 2014 article, Nunotani stated that provision of disease knowledge and information alone does not improve patients’ QOL and physical and psychological well-being [64]. Therefore, in addition to information, providing self-management techniques such as symptom self-monitoring, coping, and relaxation techniques is likely to be more effective in improving patient outcomes.

Although the most common combination of intervention categories was apparently management of psychological health together with “other,” this combination represents a diverse variety of different intervention types making it difficult to systematically analyze effective components and necessitating further study (Fig. 3). Therefore, we considered symptom management and information to be the most common effective combination, which included 10 studies [31, 37–39, 41–43, 46, 49, 55]. Among these, 6 reported decreases in healthcare resource utilization such as hospitalization and outpatient visits [39, 41–43, 49, 55]. Furthermore, in these 6 reports, HCPs explained in detail to patients how to manage their symptoms and answered patient’s questions. Additionally, the HCPs and patients shared and formed consensus on action plans and developed a plan for relapse so that patients would not have difficulty with primary management. The HCP and patients were also enabled to interactively communicate, and cooperation with family doctors was demonstrated. The intervention effectively reduced the number of outpatient visits related to the IBD. For example, the intervention of Hueppe et al. involved provision of individualized advice to patients based on automated analysis of a questionnaire to patients, which improved outcomes in health-related QOL compared with a group that received standard treatment [41]. Therefore, sharing of information and education for the purpose of symptom management may help control the severity of IBD symptoms. Besides, IBD is characterized by repeated relapses and remissions, and patient’s anxiety about relapse adversely affects their psychological condition [65]. Accordingly, symptom management is thought to lead to psychological stability. The effect of this combination of intervention types whose number was small in this study should be clarified by future studies.

Remote monitoring offers another tool for symptom management, and we identified some studies that have used digital tools to reduce the number of emergency visits or regular outpatient visits, including the interventions of De Jong et al. [42]. Hence, monitoring of a patient’s symptoms with digital tools can reduce hospitalizations and hospital visits, and symptom management using an online tool is likely to prevent relapse.

Shared Decision-Making and Team Approach

The interventions of Robinson et al. [43] and Del Hoyo et al. [49] make a case for the importance of consensus building between patient and physician. These results point to a need for patients and HCPs to share information about symptoms and jointly develop strategies to deal with IBD in life. Trivedi et al. [66] noted differences in the perception of disease “flare” and “remission” between patients and physicians and nurses, and that patient education is necessary to share information about symptoms and treatment goals with patients. Interventions classified as information provision and symptom management tended to be delivered on an individual basis, as shown in Figure 4b, and such interventions performed in a patient-participatory style were highly effective [31, 37–39, 41–43, 49, 55]. Hence, when providing information for the purposes of supporting self-management behaviors in IBD patients, in addition to unilaterally providing knowledge, HCP should listen to the patient’s experiences and tailor the information they provide according to the individual’s situation. Mutual sharing of information and experiences between the patient and HCP in this way has potential for more effective outcomes.

The elements of self-management outlined by Barlow et al. are diverse, including symptoms, psychology, diet, exercise, and social support. Hence, staff with expertise in these areas might lend greater effectiveness to their respective interventions [11]. Notably, participation of nurses has been advocated in the Nurses European Crohn’s and Colitis Organisation guidelines and previous studies [17, 67]. Kapasi et al. [68] stated that multidisciplinary interventions are necessary for high-quality patient care, and the importance of a multidisciplinary team and its format and functions has been advocated in a consensus study [69]. A coordinator is needed to practice team medical care involving many professionals, and perhaps the role is appropriate for a nurse.

Limitations

Among many of the studies examined in this analysis, investigators emphasized that variability in the baseline conditions of patients was a confounding influence on statistical significance of their outcome measures. Although general characteristics of participants were extracted, reporting on the ethnicity and active disease status was inconsistent among the studies. There was also considerable variability in the different outcome indicators used among different studies. In particular, there are no validated measures to evaluate knowledge level or the effect of educational interventions, suggesting the need for validated scales to evaluate the effects of the intervention. As an additional limitation the review considers only articles published up to June 2020; however, this scope avoids any potential influence of the COVID-19 pandemic on such interventions. In some studies, incomplete information was provided about the delivery of the interventions, including the style and time frame, highlighting a need for provision of complete details in studies to better disseminate the findings and facilitate repetition. In particular, in many studies it was unclear whether interventions were performed once or on multiple occasions; hence, no clear relationship could be found between the intervention frequency and effectiveness in the present review and further study is necessary. Few of the studies in this analysis involved social support as a component of self-management intervention but this aspect should be considered in future studies [5].

Conclusions

Self-management interventions that focus on symptom management with provision of information may support self-management of IBD patients. Such interventions might reduce use of healthcare resources and improve psychological well-being of patients. Because IBD is a highly individualized disease, it is important that interventions are delivered to patients individually by experts in each field with appropriate sharing of information with the team.

Acknowledgments

Medical writing assistance was provided by Andrew Jackson on behalf of MIMS, Japan Co. Ltd. following Good Publication Practice 3 ethical guidelines and complied with Good Publication Practice 3 ethical guidelines (Battisti et al. Ann Intern Med 163: 461–464, 2015).

Statement of Ethics

An ethics statement is not applicable because this study is based exclusively on published literature.

Conflict of Interest Statement

M.I., L.H., M. Nakashoji, and A.T. are employees of Takeda Pharmaceutical Company and J.L.F. was an employee of Takeda Pharmaceutical Company; M.N. has served as a consultant for Takeda Pharmaceutical Company; J.L.F. owns restricted stocks in Takeda Pharmaceuticals and GlaxoSmithKline.

Funding Sources

Takeda Pharmaceutical Company Limited (Tokyo, Japan) funded this collaborative research, including supporting professional data analysis and medical writing services.

Author Contributions

M.I., M. Nakashoji, and J.L.F. conceived the research. M.I., L.H., M.N., and A.T. developed and finalized the research protocol and were responsible for interpreting the results. M.I. and L.H. were responsible for data management and data analysis. M.I., L.H., M.N., and J.L.F. developed the manuscript. A.T. and J.L.F. supervised the project.

Funding Statement

Takeda Pharmaceutical Company Limited (Tokyo, Japan) funded this collaborative research, including supporting professional data analysis and medical writing services.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.